HIV protease inhibitor exposure predicts cerebral small vessel disease

Abstract

Objective HIV-associated neurocognitive disorders (HAND) remain prevalent in patients who receive highly active antiretroviral therapy (HAART) and may be associated with cumulative exposure to antiretroviral medications and other factors. We proposed that chronic toxic effects of antiretroviral drugs could contribute to cerebral small vessel disease (CSVD), which might be one of the key underpinnings of HAND. Design Clinicopathological cross-sectional study of HIV-infected adults in the California NeuroAIDS Tissue Network. Methods We employed multivariable logistic regression methods to determine associations between HAART exposure (protease inhibitor [PI]-based, non-PI-based, or no HAART) and CSVD occurrence (standard histopathology: moderate/severe, mild, or absent). We also associated HAND (relative to normal cognition) with CSVD, HIV-related neuropathologic changes, older age at death (≥50 years), sex, or hepatitis C virus infection. Results We found that both mild and moderate/severe CSVD were associated with PI-based HAART exposure after adjusting for diabetes mellitus [odds ratio (OR) 2.8 [95% confidence interval (CI) 1.03, 7.9] and 2.6 [95% CI 1.03, 6.7], respectively, n=134]. Moderate/severe CSVD was associated with diabetes after adjusting for HAART exposure (OR 7.4 [95% CI 1.6, 70.7], n=134). Notably, HAND was associated with mild CSVD (OR 4.8 [95% CI 1.1, 21.2], n=63), which remained statistically significant after adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age. Conclusion PI-based HAART exposure may increase the risk of CSVD and thereby neurocognitive impairment in HIV-infected adults. Besides the possible direct toxicity to cerebral small vessels, PI-based HAART may contribute indirectly to CSVD by inducing metabolic abnormalities.

Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years

“…43 Volumetric reductions are correlated to the frequency of white matter lesions thought to be due to SVID in HIV-uninfected study groups, providing another underlying factor that may be disproportionately present in the setting of HIV. 34,42 Our findings in both grey and white matter suggest SVID alone is insufficient to explain our findings.…”

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

“…Second, cortical deficits can develop in HAND patients, with executive function and learning ability being the most frequently affected domains [47–49]. The development of vascular cognitive impairment also poses a substantial concern, but the evidence for this is preliminary and largely obtained from neuroimaging studies [50–52]. Third, HAND can be associated with extrapyramidal features that overlap with PD [53, 54].…”

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

“…Recently it was demonstrated that mild and moderate/severe small vessel diseases were associated with protease inhibitor-based HAART exposure and that HAND was associated with mild CSVD (after adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age). [197] Further to this potentially relevant effect on cerebrovascular disease, PI-based combination treatment has been associated with reduced amyloid phagocytosis and increased neuronal accumulation justifying some of the shared and clinical features with Alzheimer's dementia. [198,199] Efavirenz effects in the CNS are well-characterized (abnormal dreams, dizziness) and associated with higher plasma concentrations and to single nucleotide polymorphisms in genes encoding for proteins involved in the drug metabolism or transport.…”